This invention relates to a novel polyether antibiotic, to a microbiological process for its production and a process for its recovery. More particularly, it relates to 19-epi-dianemycin, its production by aerobically fermenting a new strain of Streptomyces hygroscopicus, its recovery from fermentation broth, and its use as an anticoccidial agent and antibacterial agent.
Coccidiosis, a common and widespread infection in poultry, is caused by one or more of several species of protozoan parasites of the genus Eimeria. Two types of coccidiosis, cecal and intestinal, are known. The first type is caused by E. tenella and is characterized by severe hemorrhage. The second type is caused by various species of Eimeria such as E. acervulina, E. necatrix, E. maxima, E. hagani, E. mitis, E. praecox and E. brunetti. In turkeys, E. adenoides and E. maleagrimitis are causative organisms of coccidiosis.
The economic effects of coccidiosis are far-reaching and elimination or control of the disease is, therefore, of great importance to the poultry industry.
A wide variety of structural types of compounds have been described as anticoccidials including polyether antibiotics such as monensin [J. Amer. Chem. Soc., 89, 5737 (1967)]; nigericin [Biochem. Biophys. Res. Comm., 33, 29 (1968)]; grisorixin [J. Chem. Soc. Chem. Commun., 1421 (1970)]; dianemycin [J. Antibiotics 22, 161 (1969); U.S. Pat. No. 3,577,531 of May 4, 1971]; salinomycin [J. Antibiotics, 27, 814 (1974)]; X-537A [J. Chem. Soc. Chem. Commun., 967 (1972)]; X-206 [J. Chem. Soc. Chem. Commun., 927 (1971)]; A204A [J. Amer. Chem. Soc., 95, 3399 (1973)]; mutalomycin [J. Antibiotics, 30, 903 (1977)]; ionomycin [J. Amer. Chem. Soc., 101, 3344 (1979)]; K-41B [J. Antibiotics, 32, 169 (1979)]; A-130B and A- 130C J. Antibiotics 33, 94 (1980)]; leuseramycin [J. Antibiotics, 33, 137 (1980)]; and A-28695 B [J. Antibiotics, 33, 252 (1980)]. The subject has been reviewed by Westley, "Polyether Antibiotics", Adv. Appl. Microbiol., 22, 177 (1977), and by Shumard et al., Antimicrob. Agents & Chemother. 369-377 (1967).
Swine dysentery, one of the most common swine diseases diagnosed in the United States, is also prevalent in many other countries and annually causes great economic loss. It has recently been discovered that a large spirochete, Treponema hyodysenteriae, is, at the least, a primary source of the infection [Harris, D. L. et al. "Swine Dysentery-1 Inoculation of Pigs with Treponema hyodysenteriae (New Species) and Reproduction of the Disease," Vet. Med/SAC, 67, 61-64 (1972)].
Performance enhancement (increased rate of growth and/or increased efficiency of feed utilization) in ruminants, such as cattle, is another economically desirable objective of veterinary science. Of particular interest is growth promotion achieved by increasing feedutilization efficiency. The mechanism for utilization of the major nutritive portion (carbohydrates) of ruminant feeds is well known. Microorganisms in the rumen of the animals degrade carbohydrates to monosaccharides which are then converted to pyruvates. Pyruvates are metabolized by microbiological processes to form acetates, butyrates or propionates, collectively known as volatile fatty acids (VFA). For a more detailed discussion, see Leng in "Physiology of Digestion and Metabolism in the Ruminant," Phillipson et al., Eds., Oriel Press, Newcastle-upon-Tyne, England, 1970, pp. 408-410.
The relative efficiency of VFA utilization is discussed by McCullough in "Feedstuffs," June 19, 1971, page 19; Eskeland et al. in J. An. Sci. 33, 282 (1971); and Church et al. in "Digestive Physiology and Nutrition of Ruminants," Vol. 2, 1971, pp. 622 and 625. Although acetates and butyrates are utilized, propionates are utilized with greater efficiency. Furthermore, when too little propionate is available, animals may develop ketosis. A beneficial compound, therefore, stimulates animals to produce a higher proportion of propionates from carbohydrates, thereby increasing carbohydrate utilization efficiency and also reducing the incidence of ketosis.